Graeme Morgan

Nemaline myopathy: A clinical study of 143 cases

We report 143 Australian and North American cases of primary nemaline myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood‐onset, and 6 adult‐onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty‐two patients had skeletal muscle actin mutations and 4 had mutations in the α‐tropomyosinSLOW gene. Obstetric complications occurred in 49 cases. Seventy‐five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy.

Late cardiac, thyroid, and pulmonary sequelae of mantle radiotherapy for hodgkin's disease

Cardiac, thyroid and pulmonary function were evaluated in 25 patients aged 35 years or under, treated for Hodgkins disease by mantle radiotherapy 5-16 years previously. No patient had symptoms of heart disease. Although thallium myocardial perfusion scintigraphy was normal in all patients, abnormalities of myocardial function were detected in 6 (24%) patients using gated equilibrium rest and exercise radionuclide ventriculography. Resting left ventricular ejection fraction (LVEF) was abnormal in 1 patient, and in 3 patients there was an abnormal LVEF response to exercise. All 6 patients had right ventricular dilatation. Apical hypokinesia was present in 4 of these patients. A small asymptomatic pericardial effusion was detected by M-Mode echocardiography in only 2 (8%) patients. Twenty-three (92%) patients had evidence of abnormal thyroid function. Two (8%) patients had become clinically hypothyroid. Serum TSH was elevated in 13 (52%) patients and TRH stimulation test was abnormal in a further 10 (40%) patients in whom TSH was normal. Pulmonary function studies showed a moderate decrease in diffusing capacity (72% of predicted) and a minor reduction in lung volume. Although a high incidence of cardiac, thyroid and pulmonary abnormalities was detected, only the 2 patients who had become hypothyroid were symptomatic. Modification of the irradiation technique may reduce the incidence of cardiac abnormalities, but is unlikely to alter significantly the thyroid or pulmonary sequelae.

Aggressive cutaneous malignancies following cardiothoracic transplantation

The development of malignancies in recipients of a cardiothoracic transplant (CTT)—that is, heart, lung, or heart and lung recipients—is of concern. Cutaneous and lymphoproliferative malignancies comprise the two major groups of malignancies encountered. A small subgroup of patients will develop potentially life‐threatening aggressive cutaneous malignancies (ACM); these are poorly defined and documented in the literature. The authors report the results for 619 CTT recipients from a single institution.

The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.

Initial reports of patients with laminin α2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin α2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin α2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin α2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (∼6%), seizures (∼8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin α2 deficiency were asymptomatic, 10 patients had normal MRI (four withLAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin α2. In addition, the use of multiple antibodies to different regions of laminin α2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.

Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: A retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group

The curative potential of radiotherapy (RT) alone as initial treatment for patients with Stage I–II lymphocyte‐predominant Hodgkin lymphoma (LPHL) has not been defined well.

Pulmonary complications of radiation therapy

There have been important developments in understanding the difference in pathogenesis and clinical significance between acute or sporadic pneumonitis and late radiation fibrosis. Corticosteroid therapy and other forms of therapy are useful in the treatment of acute pneumonitis. Late radiation fibrosis is refractory to treatment; therefore, minimizing the likelihood of developing it is particularly important. Baseline lung assessments are appropriate in patients who are clinically at risk. A new development is the use of the DVH to compare radiation treatment plans to minimize the volume of normal lung irradiated in patients who are at risk. It is hoped that the study of mechanisms that lead to the development of radiation fibrosis will point the way to possible future therapies. Patients who are included in studies of novel irradiation treatments for lung cancer need, in particular, to be monitored for late radiation lung toxicity.

Childhood chronic inflammatory demyelinating polyneuropathy: clinical course and long-term outcome

We reviewed the clinical history, electrophysiologic and pathologic findings, and response to therapy of 16 children with chronic inflammatory demyelinating polyneuropathy. The majority presented with lower limb weakness. Sensory loss was uncommon. The illness was monophasic in seven children, relapsing in six, and three had a slowly progressive course. All patients were treated with immunosuppressive agents. In 11, the initial treatment was prednisolone. All had at least a short-term response but five went on to develop a relapsing course. Intravenous immunoglobulin was the initial treatment in four patients. Three responded rapidly, with treatment being stopped after a maximum of 5 months. In resistant chronic inflammatory demyelinating neuropathy, in addition to prednisolone and immunoglobulin, plasma exchange, azathioprine, cyclosporine, methotrexate, cyclophosphamide and pulse methylprednisolone were tried at different times in different patients. On serial neurophysiologic testing slowing of nerve conduction persisted for long periods after clinical recovery. Follow-up was for an average of 10 years. When last seen 14 patients were asymptomatic, two having mild residual deficits. Childhood chronic inflammatory demyelinating neuropathy responds to conventional treatment and generally has a favourable long-term outcome.

Radiation-Induced Lung Injury: A Hypersensitivity Pneumonitis?

Radiation pneumonitis occurs 6 to 12 weeks after thoracic irradiation, and is thought to be due to direct radiation-induced lung injury. Four patients who developed pneumonitis after unilateral thoracic irradiation for carcinoma of the breast were studied with bronchoalveolar lavage, gallium scan of the lung, and respiratory function tests. On the irradiated side of the chest, all four patients showed an increase in total cells recovered from the lavage fluid and a marked increase in the percentage of lymphocytes. When results for the unirradiated lung were compared with results for the irradiated lung, there was a comparable increase in total cells and percentage of lymphocytes. Gallium scans showed increases for both irradiated and unirradiated lungs. Prompt improvement was seen after corticosteroid therapy in all patients. The fact that abnormal findings occur equally in irradiated and unirradiated lung is inconsistent with simple direct radiation-induced injury and suggests an immunologically mediated mechanism such as a hypersensitivity pneumonitis.

Both in vitro and in vivo irradiation are associated with induction of macrophage-derived fibroblast growth factors

Fibrosis in the lung directly underlying the field of irradiation is an almost universal long term sequelae of thoracic irradiation. It is assumed to represent the consequence of direct damage to local tissues and/or vascular endothelium by ionizing radiation. This view, however, is not in keeping with our current understanding of fibrotic processes, which suggest that growth factors for fibroblasts (including platelet‐derived growth factor (PDGF), insulin‐like growth factor I (IGF‐I)) and cytokines stimulating collagen synthesis (notably transforming growth factor‐beta) are largely responsible for this process. Since a major source of these factors is the macrophage, present in large numbers within the lung, it appeared possible that radiation‐induced fibrosis might be mediated by similar mechanisms. Therefore, a study was designed to determine, first, whether in vitro irradiation of mononuclear phagocytes could induce the release of growth factors for fibroblasts. Second, we wished to ascertain whether these same growth factors might also be secreted by bronchoalveolar cells from humans who had undergone in vivo thoracic irradiation.The results of this study indicate that irradiation of a number of different types of mononuclear phagocytes resulted in the dose‐dependent synthesis and release of several growth factors for fibroblasts, including PDGF, tumour necrosis factor‐alpha (TNF‐α) and IGF‐I. Further, cells obtained by bronchoalveolar lavage from patients undergoing thoracic radiation spontaneously released PDGF following irradiation. These findings strongly support the contention that synthesis and release of macrophage‐derived growth factors for fibroblasts (particularly PDGF and IGF‐I) occur after thoracic irradiation and play a significant role in the pathogenesis of irradiation‐induced pulmonary fibrosis in humans.

Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus

The obstetric histories of 26 women with myotonic dystrophy (DM), who had a total of 67 gestations, were reviewed retrospectively comparing gestations with affected (DM-fetuses) and unaffected fetuses (UA-fetuses). Second, the influence of gestation on the disease course and the personal attitude towards family planning in DM was assessed. Miscarriages and terminations occurred in 11 pregnancies. Of the 56 infants carried to term, 29 had or most likely had inherited the gene for DM from their affected mothers at the time of investigation; 18 (61%) in this series were affected by the congenital form of DM. Perinatal loss rate was 11% and associated with congenital DM. The rate of obstetric complications was significantly increased in all women. However, preterm labor was a major problem in gestations with DM-fetuses (55 vs. 20%), as was polyhydramnios (21% vs. none). While forceps deliveries or vacuum extractions were required in 21% of deliveries with DM-fetuses and only 5% of UA-fetuses, the frequency of Cesarean sections was similar in both groups (24 and 25%). Obstetric problems were inversely correlated with age at onset of maternal DM, while no effect of age at delivery or birth order on gestational outcome was seen. DNA analysis confirmed the diagnosis in 19 patients by the presence of enlarged CTG repeats (EcoRI-expansions) on chromosome 19. Of the 17 patients whose CTG repeat length was known, 59% were classified as E2 (corresponding to 500-1000 repeats), 24% as E1 (<500 repeats), while larger expansions (E3; 1000-1500 repeats, or E4; >1500 repeats) were seen in three patients (17%). Obstetric complications or congenitally affected children occurred in all maternal phenotypes and CTG repeat classes. Eight (31%) patients experienced a worsening of symptoms that was temporary, weight related in three cases, and persistent in five. With the exception of three patients, most new mothers were able to care for their families. To conclude, pregnant women with DM need constant obstetric monitoring and should be advised to deliver in centres with perinatal facilities.